` Recommended dosage in patients with moderate and severe renal
`
`
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`
`
`daily. (2, 8.7, 8.8)
`
`
`Psoriatic Arthritis (in combination with nonbiologic DMARDs)
`
` XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`
`
`
` Recommended dosage in patients with moderate and severe renal
`
`impairment or moderate hepatic impairment is XELJANZ 5 mg once
`
`daily. (2, 8.7, 8.8)
`
`Ulcerative Colitis
`
`
` XELJANZ 10 mg twice daily for at least 8 weeks; then 5 or 10 mg
`
`
`twice daily. Discontinue after 16 weeks of 10 mg twice daily, if adequate
`
`therapeutic benefit is not achieved. Use the lowest effective dose to
`maintain response. (2.3)
`
` Recommended dosage in patients with moderate and severe renal
`
`impairment or moderate hepatic impairment: half the total daily dosage
`
`recommended for patients with normal renal and hepatic function. (2, 8.7,
`
`8.8)
`
`Dosage Adjustment
`
` See the full prescribing information for dosage adjustments by indication
`for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients
`with moderate or severe renal impairment or moderate hepatic
`
`impairment; and patients with lymphopenia, neutropenia, or anemia. (2.2,
`2.3)
`
`
` Use of XELJANZ/XELJANZ XR in patients with severe hepatic
`
`impairment is not recommended in any patient population. (2.2, 2.3, 8.8)
`
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`
`XELJANZ Tablets: 5 mg, 10 mg tofacitinib (3)
`XELJANZ XR Tablets: 11 mg tofacitinib (3)
`
` ------------------------------ CONTRAINDICATIONS ------------------------------
`
`
`None (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`
` Serious Infections: Avoid use of XELJANZ/XELJANZ XR during an
`
`active serious infection, including localized infections. (5.1)
`
`
` Gastrointestinal Perforations: Use with caution in patients that may be at
`increased risk. (5.3)
`
` Laboratory Monitoring: Recommended due to potential changes in
`lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. (5.4)
`
`Immunizations: Live vaccines: Avoid use with XELJANZ/XELJANZ
`XR. (5.5)
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`Most common adverse reactions are:
`
`
` Rheumatoid and Psoriatic Arthritis: Reported during the first 3 months in
`rheumatoid arthritis controlled clinical trials and occurring in ≥2% of
`patients treated with XELJANZ monotherapy or in combination with
`
`DMARDs: upper respiratory tract infection, nasopharyngitis, diarrhea,
`and headache. (6.1)
`
`
` Ulcerative Colitis: Reported in ≥5% of patients treated with either 5 mg or
`
`10 mg twice daily of XELJANZ and ≥1% greater than reported in patients
`
`receiving placebo in either the induction or maintenance clinical trials:
`
`nasopharyngitis, elevated cholesterol levels, headache, upper respiratory
`
`tract infection, increased blood creatine phosphokinase, rash, diarrhea,
`
`and herpes zoster. (6.1)
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`XELJANZ/XELJANZ XR safely and effectively. See full prescribing
`
`information for XELJANZ.
`
`
` XELJANZ® (tofacitinib) tablets, for oral use
`
`
`
`XELJANZ® XR (tofacitinib) extended-release tablets, for oral use
`
`Initial U.S. Approval: 2012
`
`
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`
`See full prescribing information for complete boxed warning.
`
`
`
`
` Serious infections leading to hospitalization or death, including
`
`
`tuberculosis and bacterial, invasive fungal, viral, and other
`
`opportunistic infections, have occurred in patients receiving
`
`
`XELJANZ. (5.1)
`
`
`
`
` If a serious infection develops, interrupt XELJANZ/XELJANZ XR
`
`until the infection is controlled. (5.1)
`
`
`
`
`
` Prior to starting XELJANZ/XELJANZ XR, perform a test for latent
`
`tuberculosis; if it is positive, start treatment for tuberculosis prior to
`
`
`starting XELJANZ/XELJANZ XR. (5.1)
`
`
` Monitor all patients for active tuberculosis during treatment, even if
`
`
`the initial latent tuberculosis test is negative. (5.1)
`
`
` Lymphoma and other malignancies have been observed in patients
`treated with XELJANZ. Epstein Barr Virus-associated
`
`post-transplant lymphoproliferative disorder has been observed at an
`
`
`increased rate in renal transplant patients treated with XELJANZ
`and concomitant immunosuppressive medications. (5.2)
`
`
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
`Indications and Usage (1)
`05/2018
`
`
`05/2018
`Dosage and Administration (2)
`
`
`05/2018
`Warnings and Precautions (5.1)
`
`
`12/2017
`Warnings and Precautions (5.2, 5.3)
`
`
`08/2017
`Warnings and Precautions (5.5)
`
`
` --------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`XELJANZ/XELJANZ XR is a Janus kinase (JAK) inhibitor.
`
` Rheumatoid Arthritis: XELJANZ/XELJANZ XR is indicated for the
`treatment of adult patients with moderately to severely active rheumatoid
`
`arthritis who have had an inadequate response or intolerance to
`methotrexate. It may be used as monotherapy or in combination with
`
`methotrexate or other nonbiologic disease-modifying antirheumatic drugs
`(DMARDs).
`
`
`○ Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
`with biologic DMARDs or potent immunosuppressants such as
`
`azathioprine and cyclosporine is not recommended. (1)
`
` Psoriatic Arthritis: XELJANZ/XELJANZ XR is indicated for the
`
`treatment of adult patients with active psoriatic arthritis who have had an
`
`inadequate response or intolerance to methotrexate or other
`
`
`disease-modifying antirheumatic drugs (DMARDs).
`
`
`○ Limitations of Use: Use of XELJANZ/XELJANZ XR in combination
`with biologic DMARDs or potent immunosuppressants such as
`
`azathioprine and cyclosporine is not recommended. (1)
`
` Ulcerative Colitis: XELJANZ is indicated for the treatment of adult
`
`patients with moderately to severely active ulcerative colitis (UC).
`
`
`○ Limitations of Use: Use of XELJANZ in combination with biological
`therapies for UC or with potent immunosuppressants such as
`
`azathioprine and cyclosporine is not recommended. (1)
`
`
` -----------------------DOSAGE AND ADMINISTRATION -----------------------
`
`
`Administration Instructions
`
` Do not initiate XELJANZ/XELJANZ XR if absolute lymphocyte count
`<500 cells/mm3, an absolute neutrophil count (ANC) <1000 cells/mm3 or
`
`hemoglobin <9 g/dL. (2.1)
`
`Recommended Dosage
`Rheumatoid Arthritis
`
` XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. (2.2)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at
`
`1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`
`See full prescribing information for clinically relevant drug interactions. (2, 7)
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
`Lactation: Advise not to breastfeed. (8.2)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`Reference ID: 4308396
`
`Revised: 08/2018
`
`
`
`
`
`

`

`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`
`
`1
`INDICATIONS AND USAGE
`
`
`2 DOSAGE AND ADMINISTRATION
`
`Important Administration Instructions
`2.1
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic
`Arthritis
`
`2.3 Recommended Dosage in Ulcerative Colitis
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
` Serious Infections
`5.1
`
`5.2 Malignancy and Lymphoproliferative Disorders
`
` Gastrointestinal Perforations
`5.3
`
` Laboratory Abnormalities
`5.4
`
`5.5
` Vaccinations
`5.6 Risk of Gastrointestinal Obstruction with a Non-Deformable
`Extended-Release Formulation such as XELJANZ XR
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
` Pregnancy
`8.2
` Lactation
`
`
`
`
`
`Females and Males of Reproductive Potential
`8.3
` Pediatric Use
`8.4
` Geriatric Use
`8.5
`8.6 Use in Diabetics
`
` Renal Impairment
`8.7
`
`8.8
` Hepatic Impairment
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`
`14.1 Rheumatoid Arthritis
`14.2
` Psoriatic Arthritis
`
`
` Ulcerative Colitis
`14.3
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the Full Prescribing Information
`are not listed.
`
`
`
`
`
`Reference ID: 4308396
`
`2
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: SERIOUS INFECTIONS AND MALIGNANCY
`
`
`SERIOUS INFECTIONS
`Patients treated with XELJANZ/XELJANZ XR are at increased risk for developing
`serious infections that may lead to hospitalization or death [see Warnings and Precautions
`(5.1), Adverse Reactions (6.1)]. Most patients who developed these infections were taking
`concomitant immunosuppressants such as methotrexate or corticosteroids.
`
`
`If a serious infection develops, interrupt XELJANZ/XELJANZ XR until the infection is
`controlled.
`
`
`Reported infections include:
`
`
`• Active tuberculosis, which may present with pulmonary or extrapulmonary disease.
`Patients should be tested for latent tuberculosis before XELJANZ/XELJANZ XR use
`and during therapy. Treatment for latent infection should be initiated prior to
`XELJANZ/XELJANZ XR use.
`
`
`• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with
` invasive fungal infections may present with disseminated, rather than localized, disease.
`
`
`• Bacterial, viral, including herpes zoster, and other infections due to opportunistic
`pathogens.
`
`
`
`The risks and benefits of treatment with XELJANZ/XELJANZ XR should be carefully
`considered prior to initiating therapy in patients with chronic or recurrent infection.
`
`Patients should be closely monitored for the development of signs and symptoms of
`infection during and after treatment with XELJANZ/XELJANZ XR, including the possible
`development of tuberculosis in patients who tested negative for latent tuberculosis infection
`prior to initiating therapy [see Warnings and Precautions (5.1)].
`
`
`MALIGNANCIES
`Lymphoma and other malignancies have been observed in patients treated with
`XELJANZ. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder
`
`has been observed at an increased rate in renal transplant patients treated with XELJANZ
`and concomitant immunosuppressive medications [see Warnings and Precautions (5.2)].
`
`
`
`1 INDICATIONS AND USAGE
`
`Rheumatoid Arthritis
`XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to
`severely active rheumatoid arthritis who have had an inadequate response or intolerance to
`methotrexate. It may be used as monotherapy or in combination with methotrexate or other
`nonbiologic disease-modifying antirheumatic drugs (DMARDs).
`
`Reference ID: 4308396
`
`3
`
`
`

`

`
`
`
` Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic
`DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not
`recommended.
`
`
`Psoriatic Arthritis
`XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic
`arthritis who have had an inadequate response or intolerance to methotrexate or other
`disease-modifying antirheumatic drugs (DMARDs).
`
` Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic
`DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not
`recommended.
`
`
`Ulcerative Colitis
`
`XELJANZ is indicated for the treatment of adult patients with moderately to severely active
`ulcerative colitis (UC).
`
`
` Limitations of Use: Use of XELJANZ in combination with biological therapies for UC or
`with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Important Administration Instructions
`
` Do not initiate XELJANZ/XELJANZ XR in patients with an absolute lymphocyte count
`less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3 or
`who have hemoglobin levels less than 9 g/dL.
`
` Dose interruption is recommended for management of lymphopenia, neutropenia, and
`anemia [see Warnings and Precautions (5.4), Adverse Reactions (6.1)].
`Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until
`
` the infection is controlled [see Warnings and Precautions (5.1)].
`
` Take XELJANZ/XELJANZ XR with or without food [see Clinical Pharmacology
`
`(12.3)].
`
`
` Swallow XELJANZ XR tablets whole and intact. Do not crush, split, or chew.
`
`
`
`
`
`2.2 Recommended Dosage in Rheumatoid Arthritis and Psoriatic Arthritis
`
`
`Table 1 displays the recommended adult daily dosage of XELJANZ and XELJANZ XR and
`dosage adjustments for patients receiving CYP2C19 and/or CYP3A4 inhibitors, in patients with
`moderate or severe renal impairment or moderate hepatic impairment, with lymphopenia,
`neutropenia, or anemia.
`
`
`Reference ID: 4308396
`
`4
`
`
`

`

`
`
`
`Adult patients
`
`Patients receiving:
`
` Strong CYP3A4 inhibitors (e.g.,
`
`ketoconazole), or
`
` a moderate CYP3A4 inhibitor(s)
`
`with a strong CYP2C19
`
`
`inhibitor(s) (e.g., fluconazole)
`
`
`[see Drug Interactions (7)]
`
`Patients with:
`
`
` moderate or severe renal
`
`impairment [see Use in Specific
`
`
`Populations (8.7)]
`
`
` moderate hepatic impairment
`
`[see Use in Specific Populations
`(8.8)]*
`Patients with lymphocyte count less
`
` than 500 cells/mm3, confirmed by
`repeat testing
`Patients with ANC 500 to
`1000 cells/mm3
`
`Table 1: Recommended Dosage of XELJANZ and XELJANZ XR in Patients with
`Rheumatoid Arthritis1 and Psoriatic Arthritis2
`
`
` XELJANZ
`
`5 mg twice daily
`
` XELJANZ XR
`
`
`11 mg once daily
`
`
`5 mg once daily
`
`
`Switch to
`
`
`XELJANZ 5 mg once daily
`
`
`5 mg once daily
`
`
`Switch to
`
`
`XELJANZ 5 mg once daily
`
`
`
` Discontinue dosing.
`
`Interrupt dosing.
`Interrupt dosing.
`
`
`When ANC is greater than 1000,
`When ANC is greater than 1000,
`
`resume 5 mg twice daily.
`resume 11 mg once daily.
`Discontinue dosing.
`
`
`Interrupt dosing until hemoglobin values have normalized.
`
`
`
`
`Patients with ANC less than
`
`500 cells/mm3
`Patients with hemoglobin less than
`8 g/dL or a decrease of more than
`
`2 g/dL
`
`
` 1 XELJANZ/XELJANZ XR may be used as monotherapy or in combination with methotrexate or other
` nonbiologic disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis.
`
`
`2 XELJANZ/XELJANZ XR is used in combination with nonbiologic disease modifying antirheumatic drugs
`
`
`
`(DMARDs) in psoriatic arthritis. The efficacy of XELJANZ/XELJANZ XR as a monotherapy has not been
`
`studied in psoriatic arthritis.
`* Use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended.
`
`
`
`
`
`
`
`
`Switching from XELJANZ Tablets to XELJANZ XR Tablets
`Patients treated with XELJANZ 5 mg twice daily may be switched to XELJANZ XR 11 mg once
`daily the day following the last dose of XELJANZ 5 mg.
`
`2.3 Recommended Dosage in Ulcerative Colitis
`Table 2 displays the recommended adult daily dosage of XELJANZ and dosage adjustments for
`
`patients receiving CYP2C19 and/or CYP3A4 inhibitors, with moderate or severe renal
`
`impairment or moderate hepatic impairment, with lymphopenia, neutropenia or anemia.
`
`
`Reference ID: 4308396
`
`5
`
`
`

`

`
`
`Table 2: Recommended Dosage of XELJANZ in Patients with UC
`
`
`Ulcerative Colitis
` XELJANZ
`
`
`
`
`10 mg twice daily for at least 8 weeks; followed by 5 or 10 mg twice
`Adult patients
`daily, depending on therapeutic response [see Clinical Studies (14.3)].
`
`Use the lowest effective dose to maintain response [see Warnings and
`
`Precautions (5.1, 5.2, 5.4)].
`
`
`
`
`Discontinue XELJANZ after 16 weeks of treatment with 10 mg twice
`
`daily, if adequate therapeutic benefit is not achieved.
`
`
`Patients receiving:
`
` Strong CYP3A4 inhibitors (e.g.,
`
`ketoconazole), or
`
` a moderate CYP3A4 inhibitor(s)
`with a strong CYP2C19 inhibitor(s)
`
`(e.g., fluconazole)
`
`[see Drug Interactions (7)]
`
`
`Patients with:
`
`
` moderate or severe renal impairment
`
`[see Use in Specific Populations
`
`(8.7)]
`
` moderate hepatic impairment [see
`
`
`
`Use in Specific Populations (8.8)]*
`Patients with lymphocyte count less
`
` than 500 cells/mm3, confirmed by
`repeat testing
`Patients with ANC 500 to
`1000 cells/mm3
`
`
`
`
`If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
`
`If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`
`
`
`If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
`
`If taking 5 mg twice daily, reduce to 5 mg once daily.
`
`
`
` Discontinue dosing.
`
` If taking 10 mg twice daily, reduce to 5 mg twice daily.
`
`
`
`
` When ANC is greater than 1000, increase to 10 mg twice daily based
`on clinical response.
`
`If taking 5 mg twice daily, interrupt dosing. When ANC is greater than
`
`
`
`
`1000, resume 5 mg twice daily.
`Discontinue dosing.
`
`
`
`Patients with ANC less than
`
`500 cells/mm3
`Patients with hemoglobin less than 8
`Interrupt dosing until hemoglobin values have normalized.
`g/dL or a decrease of more than 2 g/dL
`
`
`*Use in patients with severe hepatic impairment is not recommended.
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`XELJANZ Tablets:
`
`
`○ 5 mg tofacitinib: White, round, immediate-release film-coated tablets, debossed with
`
`“Pfizer” on one side, and “JKI 5” on the other side.
`
`
`
`
`○ 10 mg tofacitinib: Blue, round, immediate-release film-coated tablets, debossed with
`“Pfizer” on one side, and “JKI 10” on the other side.
`
`Reference ID: 4308396
`
`6
`
`
`

`

`
`
`
`XELJANZ XR Tablets:
`
` 11 mg tofacitinib: Pink, oval, extended-release film-coated tablets with a drilled hole at
`
`one end of the tablet band and “JKI 11” printed on one side of the tablet.
`
`
`
`4 CONTRAINDICATIONS
`
`None.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Serious Infections
`Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or
`other opportunistic pathogens have been reported in patients receiving XELJANZ. The most
`common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes
`zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections,
`tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal
`candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK
`virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with
`disseminated rather than localized disease, and were often taking concomitant
`
`immunomodulating agents such as methotrexate or corticosteroids.
`
`In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater
`
`risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster
`infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were
`seen in patients who were treated with XELJANZ 10 mg twice daily.
`
`Other serious infections that were not reported in clinical studies may also occur (e.g.,
`
`coccidioidomycosis).
`
`Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including
`localized infections. The risks and benefits of treatment should be considered prior to initiating
`XELJANZ/XELJANZ XR in patients:
`• with chronic or recurrent infection
`
`
`• who have been exposed to tuberculosis
`
`• with a history of a serious or an opportunistic infection
`
`• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
`
`• with underlying conditions that may predispose them to infection.
`
`
`Patients should be closely monitored for the development of signs and symptoms of infection
`during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be
`interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A
`patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should
`undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient;
`
`Reference ID: 4308396
`
`7
`
`
`

`

`
`
`appropriate antimicrobial therapy should be initiated, and the patient should be closely
`monitored.
`
`Caution is also recommended in patients with a history of chronic lung disease, or in those who
`develop interstitial lung disease, as they may be more prone to infections.
`
`Risk of infection may be higher with increasing degrees of lymphopenia and consideration
`should be given to lymphocyte counts when assessing individual patient risk of infection.
`Discontinuation and monitoring criteria for lymphopenia are recommended [see Dosage and
`Administration (2.2, 2.3)].
`
`
`Tuberculosis
`Patients should be evaluated and tested for latent or active infection prior to and per applicable
`guidelines during administration of XELJANZ/XELJANZ XR.
`
`Anti-tuberculosis therapy should also be considered prior to administration of
`XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom
`
`an adequate course of treatment cannot be confirmed, and for patients with a negative test for
`latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a
`physician with expertise in the treatment of tuberculosis is recommended to aid in the decision
`about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
`
`Patients should be closely monitored for the development of signs and symptoms of tuberculosis,
`including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
`
`Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before
`administering XELJANZ/XELJANZ XR.
`
`
`Viral Reactivation
`
`Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were
`observed in clinical studies with XELJANZ. The impact of XELJANZ/XELJANZ XR on
`chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or
`C were excluded from clinical trials. Screening for viral hepatitis should be performed in
`accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The
`risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears
`
`to be higher in patients treated with XELJANZ in Japan and Korea.
`
`5.2 Malignancy and Lymphoproliferative Disorders
`Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy
`in patients with a known malignancy other than a successfully treated non-melanoma skin cancer
`(NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a
`malignancy. Malignancies were observed in clinical studies of XELJANZ [see Adverse
`Reactions (6.1)].
`
`
`
`In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma
`were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to
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`0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group
`during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in
`the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.
`
`During the 2 PsA controlled clinical studies there were 3 malignancies (excluding NMSC) in
`474 patients receiving XELJANZ plus nonbiologic DMARD (6 to 12 months exposure)
`compared with 0 malignancies in 236 patients in the placebo plus nonbiologic DMARD group
`(3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus nonbiologic
`DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also
`been observed in the long-term extension study in psoriatic arthritis patients treated with
`XELJANZ.
`
`
`During the UC controlled clinical studies (8-week induction and 52-week maintenance studies),
`
`which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in
`
`XELJANZ-treated patients. In the long-term extension study, malignancies (including solid
`
`
`cancers and lymphomas) were observed more often in patients treated with XELJANZ 10 mg
`
`
`
`twice daily.
`
`
`
`In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom
`
`
`received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid
`
`products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was
`
`observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of
`
`111 patients treated with cyclosporine.
`
`
`Other malignancies were observed in clinical studies and the post-marketing setting, including,
`
`
`but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
`
`
`Non-Melanoma Skin Cancer
`
`Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ.
`
`Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
`
`
`In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater
`
`risk of NMSC.
`
`
`5.3 Gastrointestinal Perforations
`Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ,
`although the role of JAK inhibition in these events is not known. In these studies, many patients
`with rheumatoid arthritis were receiving background therapy with Nonsteroidal
`Anti-Inflammatory Drugs (NSAIDs).
`
`There was no discernable difference in frequency of gastrointestinal perforation between the
`placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were
`receiving background corticosteroids.
`
`XELJANZ/XELJANZ XR should be used with caution in patients who may be at increased risk
`for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).
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`Patients presenting with new onset abdominal symptoms should be evaluated promptly for early
`identification of gastrointestinal perforation [see Adverse Reactions (6.1)].
`
`
`5.4 Laboratory Abnormalities
`
`Lymphocyte Abnormalities
`Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure
`followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of
`approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3
`were associated with an increased incidence of treated and serious infections.
`
`Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count
`(i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count
`less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.
`
`Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended
`modifications based on lymphocyte counts [see Dosage and Administration (2.2, 2.3)].
`
`Neutropenia
`Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than
`
`2000 cells/mm3) compared to placebo.
`
`Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count
`(i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500 to
`1000 cells/mm3, interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to
`1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with
`XELJANZ/XELJANZ XR is not recommended.
`
`Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months
`thereafter. For recommended modifications based on ANC results [see Dosage and
`Administration (2.2, 2.3)].
`
`Anemia
`Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level
`(i.e., less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in
`patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops
`greater than 2 g/dL on treatment.
`
`Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.
`For recommended modifications based on hemoglobin results [see Dosage and Administration
`(2)].
`
`Liver Enzyme Elevations
`
`Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation
`compared to placebo. Most of these abnormalities occurred in studies with background DMARD
`(primarily methotrexate) therapy.
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`Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme
`
` elevations is recommended to identify potential cases of drug-induced liver injury. If
`drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be
`interrupted until this diagnosis has been excluded.
`
`Lipid Elevations
`Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters
`including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density
`lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There
`were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid
`parameter elevations on cardiovascular morbidity and mortality has not been determined.
`
`Assessment of lipid parameters should be performed approximately 4-8 weeks following
`initiation of XELJANZ/XELJANZ XR therapy.
`
`Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program
`
`(NCEP)] for the management of hyperlipidemia.
`
`5.5 Vaccinations
`Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between
`live vaccinations and initiation of tofacitinib therapy should be in accordance with current
`vaccination guidelines regarding immunosuppressive agents.
`
`
`A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after
`vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with
`tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous
`history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was
`discontinued and the patient recovered after treatment with standard doses of antiviral
`medication.
`
`Update immunizations in agreement with current immunization guidelines prior to initiating
`XELJANZ/XELJANZ XR therapy.
`
`5.6 Risk of Gastrointestinal Obstruction with a Non-Deformable Extended-Release
`Formulation such as XELJANZ XR
`As with any other non-deformable material, caution should be used when administering
`XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or
`iatrogenic). There have been rare reports of obstructive symptoms in patients with known
`strictures in association with the ingestion of other drugs utilizing a non-deformable
`extended-release formulation.
`
`
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`6 ADVERSE REACTIONS
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
` Serious Infections [see Warnings and Precautions (5.1)]
`
`
` Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.2)]
`
`
` Gastrointestinal Perforations [see Warnings and Precautions (5.3)]
`
`
` Laboratory Abnormalities [see Warnings and Precautions (5.4)]
`
`
`
`6.1 Clinical Trials Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction rates
`
`observed in the clinical studies of a drug cannot be directly compared to rates in the clinical
`
`studies of another drug and may not predict the rates observed in a broader patient population in
`
`clinical practice.
`
`
`
`Rheumatoid Arthritis
`
`
`The clinical studies described in the following sections were conducted using XELJANZ.
`
`Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is
`
`5 mg twice daily.
`
`
`The recommended dose for XELJANZ XR is 11 mg once daily.
`
`The following data includes two Phase 2 and five Phase 3 doub